The overall hypothesis of this proposal is that regional variations in 5-HT release are important determinants of the response to SSRIs and behavioral reactivity to stress and environmental stimuli. The results for our prior in vivo microdialysis and behavior studies in 5-HT receptor mutants guide the objectives for this renewal proposal. The first objective is to employ targeted pharmacological challenge procedures to establish that 5-HT efflux in different brain regions is regulated in a topographical pattern and to determine the extent that different 5-HT autoreceptors contribute to these regional effects. The second objective is to provide new information concerning the circuitry by which 5-HT1A receptors regulate 5-HT transmission and compensations for their absence using tissue specific and temporally inducible genetic deletion. The third objective will be to examine the efflux of 5-HT in different brain regions of wild-type and mutant mice during performance of behaviors on tests for anxiety and antidepressants. The final objective will be to examine interactions with catecholamine neurotransmitters that may be important for regulating 5-HT efflux. Taken together, the proposed research program will continue to examine systematically the utility of genetic regulation for determining specific changes in 5-HT release and behavior is that is related to the expression of affective behaviors and the effects of antidepressant drugs.